1. Field of the Invention
The present invention relates to a method for examining the involvement of opioids in diseases.
2. Description of the Related Art
Recently, it has become evident that opioids have a wide variety of biological activities. For examples, opioids are not only involved in pain, but also act upon the immune system (T. Hosokawa et al., Pain Clinic, 21, 857–864, 2000). However, roles which the opioids play in vivo have not been sufficiently clarified other than those in pain. For example, the relation of the opioids with itching (pruritus) is now being clarified, while itching is considered to be close to pain.
Itching (pruritus) is a sensation which is unique to skin, and is mostly observed in a variety of dermatoses attended with inflammation. However, such itching is also induced by some internal diseases (e.g., malignant tumor, diabetes, hepatic diseases, renal failure, hemodialysis, peritoneal dialysis, gout, diseases of the thyroid, blood disorders, and sideropenia) or by pregnancy or vermination. In addition, it is sometimes caused by medicaments or is psychogenically caused. Itching is a subjective sensation and cannot be objectively quantitatively assessed. How and in which mechanism itching manifests has not yet been sufficiently clarified.
For pruritus therapy, antihistaminic agents or antiallergic agents are mainly used as oral medicines, and antihistaminic agents, adrenocortic steroidal medicines for external application, nonsteroidal antiphlogistics, camphor, menthol, phenol, salicylic acid, rectified tar oil, crotamiton, capsaicin, moisture-retentive agents (e.g., urea, Hirudoid (trade name; a heparinoid from animal organs, available from Maruho Co., Ltd.), and Vaseline). Of these therapeutic agents, only antihistaminic agents against urticaria are accepted to have a sufficient therapeutic efficacy. Other agents are not always sufficient in therapeutic efficacy in many cases (Y. Miyaji, Itching Q & A, p. 20, 1997, Iyaku (Medicine and Drug) Journal Co., Ltd.). The reason for this phenomenon is that inflammatory mediators such as histamine have been considered to be a main cause of itching, and antihistaminic agents and antiallergic agents serving as antagonists against these mediators have therefore been developed as therapeutic agents for pruritus.
At present, histamine, serotonin, substance P, bradykinin, proteinases, prostaglandins, and opioid peptides are known as stimulators to initiate itching. The itching sensation is considered to be initiated by the following mechanism. Specifically, itching stimulators act upon nerve endings (itching receptors) which reside in the epidermis-dermis interface, are composed of C fibers and are responsible to multi-stimulation. The resulting impulses are transmitted to afferent C fibers and reach the spinothalamic tract, thalamus and cerebral cortex in this order to induce itching (Y. Miyaji; Approach to Treatment of Skin Pruritus, p. 22, 1996, Sentan-Igaku (Advanced Medicine) Co Ltd.).
Some opioids have been known to be involved in inducement of itching. For example, it has been reported that endogenous opioids such as β-endorphin and enkephalin induce itching (B. Fjeller; Acta, Dermato-Venereol., 61 (suppl. 97), 1–34, 1981). In addition, it has been clarified that the epidural or intraspinal administration of morphine or an opioid compound initiates itching as an adverse drug reaction (J. H. Jaffe and W. R. Martin; Goodman and Gilman's Pharmacological Basis of Therapeutics, Macmillan, N.Y., 1985). On the other hand, it has been clarified that itching initiated by the intraspinal administration of morphine is inhibited by naloxone, a morphine antagonist (J. Bernstein et al.; J. Invest. Dermatol., 78, 82–83, 1982) and that a severe itching in a patient with hepatopathic cholestasia, which is firmly suggested to be induced by an increased enkephalin, is inhibited by an opioid antagonist nalmefene (J. R. Thornton and M. S. Losowsky; Br. Med. J., 297, 1501–1504, 1988). It is therefore the consensus view that opioid agonists act to initiate itching and, in contrast, opioid antagonists have an antipruritic activity. In addition, it has been reported that the serum concentrations of β-endorphin in children with atopic dermatitis are significantly higher than those in healthy children and that opioid antagonists may be effective against itching (S. Georgala et al.; J. Dermatol. Sci., 8, 125–128, 1994).
Based on these findings, itching is considered to be caused by chemical mediators such as histamine in some cases and by opioids such as morphine, β-endorphin, and other μ (mu) opioid receptor agonists or μ-opioid peptides in other cases (K. Takamori; Dermatological Diagnosis and Treatment Practice 6: Atopic Dermatitis, p. 79, 1999, Bunkodo Co., Ltd.).
As such opioid receptors, μ-, κ- (kappa), δ- (delta), and ORL-1 (nociceptin) receptors are known, and endogenous opioid peptides that respectively selectively stimulate individual receptors have been found. For example, μ- and δ-receptor agonistic endogenous opioid peptides include β-endorphin and enkephalin, respectively, and κ-receptor agonistic endogenous opioid peptides include dynorphin, and ORL-1 receptor agonistic endogenous opioid peptides include nociceptin. Of these opioid peptides, α-endorphin is known as an opioid peptide which possibly invites itching. In contrast, κ-opioid agonists have been found to inhibit itching in recent years (PCT International Publication No. 98/23290), suggesting a possibility that κ-receptor agonistic endogenous peptides inhibit itching.
As described above, histamine and other chemical mediators, and opioids are considered to be candidates of causes of itching, and a therapy should be naturally selected depending on the cause. However, a method for selecting an appropriate therapy depending on the cause of itching has not yet been found.